According to the Centers for Disease Control and Prevention (CDC), in the United States alone there are more than 2.5 million reported cases of traumatic brain injury (TBI) each year. It is believed that more than 5 to 6 million cases of TBI in the United States per year go unreported because they are not believed to be severe enough to be treated in hospital settings, designated as mild TBI (mTBI), and are thus treated in non-hospital settings or not treated at all. These statistics do not include the many TBI events, both mTBI and more severe TBI, suffered by our military personnel daily in the many conflicts that they are involved in outside the United States. These statistics also do not include the TBI events suffered by others outside the United States. It is only recently that the medical community has come to realize that the consequences of so called mild TBI may not be mild in the longer term. Epidemiological research has identified mTBI as a major public health concern. Clinical research evidence has emerged suggesting that for some patients even mTBI in addition to more severe TBI can lead to prolonged physical and neurocognitive symptoms months to years after the brain injury has occurred. The neuropathology of human TBI is characterized by diffuse axonal injury leading to alterations of functional connectivity of various brain regions and prolonged neuroinflammation as evidenced by reactive astrocytes, activated microglia, and microbleeds in gray matter regions and white matter tracts.
Acute and chronic brain injuries and degenerative disorders can activate resident brain cells such as astrocytes and microglia and recruit peripheral immune cells to injured brain regions resulting in amplified neuroinflammation and exacerbation of brain damage. Leukotrienes (LT) are potent bioactive lipids that mediate inflammation. Murphy R C, et a. Proc Natl Acad Sci USA. 76:4275-4279, 1979. Leukotriene biosynthesis is initiated by mechanical injury to cells and enzymatic cleavage of arachidonic acid (AA) from membrane glycerolphospholipids. Falco, G and Murphy R C, Pharmacol, Rev. 58, 375-388, 2006. The enzymatic action of 5-lipoxygenase (5-LO) and 5-lipoxygenase activating protein (FLAP) converts AA into leukotriene A4 (LTA4). The LTA4 is quickly converted to leukotriene B4 (LTB4) by LTA4-hydrolase or to leukotriene C4 (LTC4) by LTC4-synthase. LTC4 can then be converted to leukotriene D4 (LTD4) and leukotriene E4 (LTE4), and these three LTs (LTC4, LTD4, LTE4) are collectively known as the cysteinyl leukotrienes. The actions of cysteinyl leukotrienes have been studied primarily in the context of asthma where they are known to induce vascular permeability, extravasation of large molecules, stimulation of cytokine release, and contraction of bronchial smooth muscle. Boyce J A, Immunol. Rev. 217, 168-185, 2007. Leukotrienes are undetectable in the healthy brain. Farias S, et al, J. Neurotraum, 26, 1977-1986, 2009. After traumatic brain injury (TBI) or stroke, however, leukotrienes are synthesized by a transcellular mechanism involving infiltrating neutrophils or endogenous microglia and endogenous brain cells. Farias S, J. Neurochem. 103, 1310-1318, 2007; Farias S, et al. J. Neurotraum. 26, 1977-1986, 2009.
It is desirable to provide a method to ameliorate the neuroinflammation and neurodegeneration that accompanies brain injury events such as TBI, stroke, multiple sclerosis, and Alzheimer's disease. In addition, some recent research seems to suggest that posttraumatic stress disorder (PTSD) may have a neurodegeneration component to it and thus it is also a potential candidate for a method to reduce neurodegeneration and neuroinflammation. It would be beneficial to prevent a range of the secondary physical effects and cognitive effects of these brain injury events.